tbuckley/cabot-search huggingface dataset:
Childhood Non-HDL Cholesterol and LDL Cholesterol and Adult Atherosclerotic Cardiovascular Events
Authors: Feitong Wu, Markus Juonala, David R. Jacobs, Stephen R. Daniels, Mika Kähönen, Jessica G. Woo, Alan R. Sinaiko, Jorma S.A. Viikari, Lydia A. Bazzano, Trudy L. Burns, Julia Steinberger, Elaine M. Urbina, Alison J. Venn, Olli T. Raitakari, Terence Dwyer, Costan G. Magnussen
Journal: Circulation (2023)

BACKGROUND: Although low-density lipoprotein cholesterol (LDL-C) remains the primary cholesterol target in clinical practice in children and adults, non–high-density lipoprotein cholesterol (non–HDL-C) has been suggested as a more accurate measure of atherosclerotic cardiovascular disease (ASCVD) risk. We examined the associations of childhood non–HDL-C and LDL-C levels with adult ASCVD events and determined whether non–HDL-C has better utility than LDL-C in predicting adult ASCVD events. METHODS: This prospective cohort study included 21 126 participants from the i3C Consortium (International Childhood Cardiovascular Cohorts). Proportional hazards regressions were used to estimate the risk for incident fatal and fatal/nonfatal ASCVD events associated with childhood non–HDL-C and LDL-C levels (age- and sex-specific z scores; concordant/discordant categories defined by guideline-recommended cutoffs), adjusted for sex, Black race, cohort, age at and calendar year of child measurement, body mass index, and systolic blood pressure. Predictive utility was determined by the C index. RESULTS: After an average follow-up of 35 years, 153 fatal ASCVD events occurred in 21 126 participants (mean age at childhood visits, 11.9 years), and 352 fatal/nonfatal ASCVD events occurred in a subset of 11 296 participants who could be evaluated for this outcome. Childhood non–HDL-C and LDL-C levels were each associated with higher risk of fatal and fatal/nonfatal ASCVD events (hazard ratio ranged from 1.27 [95% CI, 1.14–1.41] to 1.35 [95% CI, 1.13–1.60] per unit increase in the risk factor z score). Non–HDL-C had better discriminative utility than LDL-C (difference in C index, 0.0054 [95% CI, 0.0006–0.0102] and 0.0038 [95% CI, 0.0008–0.0068] for fatal and fatal/nonfatal events, respectively). The discordant group with elevated non–HDL-C and normal LDL-C had a higher risk of ASCVD events compared with the concordant group with normal non–HDL-C and LDL-C (fatal events: hazard ratio, 1.90 [95% CI, 0.98–3.70]; fatal/nonfatal events: hazard ratio, 1.94 [95% CI, 1.23–3.06]). CONCLUSIONS: Childhood non–HDL-C and LDL-C levels are associated with ASCVD events in midlife. Non–HDL-C is better than LDL-C in predicting adult ASCVD events, particularly among individuals who had normal LDL-C but elevated non–HDL-C. These findings suggest that both non–HDL-C and LDL-C are useful in identifying children at higher risk of ASCVD events, but non–HDL-C may provide added prognostic information when it is discordantly higher than the corresponding LDL-C and has the practical advantage of being determined without a fasting sample.
Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement From the American Heart Association and Neurocritical Care Society
Authors: Karen G. Hirsch, Benjamin S. Abella, Edilberto Amorim, Mary Kay Bader, Jeffrey F. Barletta, Katherine Berg, Clifton W. Callaway, Hans Friberg, Emily J. Gilmore, David M. Greer, Karl B. Kern, Sarah Livesay, Teresa L. May, Robert W. Neumar, Jerry P. Nolan, Mauro Oddo, Mary Ann Peberdy, Samuel M. Poloyac, David Seder, Fabio Silvio Taccone, Anezi Uzendu, Brian Walsh, Janice L. Zimmerman, Romergryko G. Geocadin
Journal: Circulation (2023)

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.
Brief Report: Real-World Toxicity and Survival of Combination Immunotherapy in Pleural Mesothelioma—RIOMeso
Authors: Nicholas McNamee, Catriona Harvey, Lauren Gray, Trisha Khoo, Lavanya Lingam, Betty Zhang, Udit Nindra, Po Yee Yip, Abhijit Pal, Timothy Clay, Surein Arulananda, Malinda Itchins, Nick Pavlakis, Steven Kao, Samantha Bowyer, Venessa Chin, Lydia Warburton, Inês Pires da Silva, Thomas John, Benjamin Solomon, Marliese Alexander, Adnan Nagrial
Journal: Journal of Thoracic Oncology (2023)
Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors
Authors: Yulu Chen, Antonio Checa, Pei Zhang, Mengna Huang, Rachel S. Kelly, Min Kim, Yih‐Chieh S. Chen, Kathleen A. Lee‐Sarwar, Nicole Prince, Kevin M. Mendez, Sofina Begum, Priyadarshini Kachroo, Su H. Chu, Jakob Stokholm, Klaus Bønnelykke, Augusto A. Litonjua, Hans Bisgaard, Scott T. Weiss, Bo L. Chawes, Craig E. Wheelock, Jessica A. Lasky‐Su
Journal: Allergy (2023)

Abstract Background While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship. Method s We performed targeted LC–MS/MS‐based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC 2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3 , low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta‐analyzed together. Results We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p ‐value range: 1.863E‐04 to 2.24E‐3], increased ceramide levels were associated with asthma risk factors [meta p ‐value range: 7.75E‐5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes. Conclusion This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.
Dupilumab demonstrated efficacy and was well tolerated regardless of prior use of swallowed topical corticosteroids in adolescent and adult patients with eosinophilic oesophagitis: a subgroup analysis of the phase 3 LIBERTY EoE TREET study
Authors: Albert J Bredenoord, Evan S Dellon, Ikuo Hirano, Alfredo J Lucendo, Christoph Schlag, Xian Sun, Lila Glotfelty, Leda Mannent, Jennifer Maloney, Elizabeth Laws, Eric Mortensen, Arsalan Shabbir
Journal: Gut (2023)

Objective To assess the effect of long-term dupilumab on histological, symptomatic and endoscopic aspects of eosinophilic oesophagitis (EoE) in adolescent and adult patients with and without prior use of swallowed topical corticosteroids (STC) or prior inadequate response, intolerance or contraindication to STC. Design Pre-specified analysis of data from the phase 3 LIBERTY EoE TREET study on patients who received dupilumab 300 mg once a week or placebo for 24 weeks (W24) in parts A and B, and an additional 28 weeks (W52) in part C. Patients were categorised as with/without prior STC use and with/without inadequate/intolerance/contraindication to STC. The proportion of patients achieving ≤6 eosinophils per high-power field (eos/hpf), absolute change in Dysphagia Symptom Questionnaire (DSQ) score, mean change in Endoscopic Reference Score and Histologic Scoring System grade/stage scores were assessed for each subgroup. Results Regardless of prior STC use, dupilumab increased the proportion of patients achieving ≤6 eos/hpf and improved DSQ score versus placebo at W24, with improvements maintained or improved at W52. The DSQ score and the proportion of patients achieving ≤6 eos/hpf after switching from placebo to dupilumab at W24 were similar to those observed in the dupilumab group at W24, regardless of prior STC use or inadequate/intolerance/contraindication to STC. Improvements in other outcomes with dupilumab were similar in patients with/without prior STC use or inadequate/intolerance/contraindication to STC. Conclusion Dupilumab 300 mg once a week demonstrated efficacy and was well tolerated in patients with EoE regardless of prior STC use or inadequate response, intolerance and/or contraindication to STC. Trial registration number NCT03633617 .
Actigraphy-derived measures of sleep and risk of prostate cancer in the UK Biobank
Authors: Joshua R Freeman, Pedro F Saint-Maurice, Eleanor L Watts, Steven C Moore, Marissa M Shams-White, Dana L Wolff-Hughes, Daniel E Russ, Jonas S Almeida, Neil E Caporaso, Hyokyoung G Hong, Erikka Loftfield, Charles E Matthews
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Studies of sleep and prostate cancer are almost entirely based on self-report, with limited research using actigraphy. Our goal was to evaluate actigraphy-measured sleep and prostate cancer and to expand on findings from prior studies of self-reported sleep. Methods We prospectively examined 34 260 men without a history of prostate cancer in the UK Biobank. Sleep characteristics were measured over 7 days using actigraphy. We calculated sleep duration, onset, midpoint, wake-up time, social jetlag (difference in weekend-weekday sleep midpoints), sleep efficiency (percentage of time spent asleep between onset and wake-up time), and wakefulness after sleep onset. Cox proportional hazards models were used to estimate covariate-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). Results Over 7.6 years, 1152 men were diagnosed with prostate cancer. Sleep duration was not associated with prostate cancer risk. Sleep midpoint earlier than 4:00 am was not associated with prostate cancer risk, though sleep midpoint of 5:00 am or later was suggestively associated with lower prostate cancer risk but had limited precision (earlier than 4:00 am vs 4:00-4:59 am HR = 1.00, 95% CI = 0.87 to 1.16; 5:00 am or later vs 4:00-4:59 am HR = 0.79, 95% CI = 0.57 to 1.10). Social jetlag was not associated with greater prostate cancer risk (1 to &amp;lt;2 hours vs &amp;lt;1 hour HR = 1.06, 95% CI = 0.89 to 1.25; ≥2 hours vs &amp;lt;1 hour HR = 0.90, 95% CI = 0.65 to 1.26). Compared with men who averaged less than 30 minutes of wakefulness after sleep onset per day, men with 60 minutes or more had a higher risk of prostate cancer (HR = 1.20, 95% CI = 1.00 to 1.43). Conclusions Of the sleep characteristics studied, higher wakefulness after sleep onset—a measure of poor sleep quality—was associated with greater prostate cancer risk. Replication of our findings between wakefulness after sleep onset and prostate cancer are warranted.
Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy
Authors: Matin Chehelgerdi, Fereshteh Behdarvand Dehkordi, Mohammad Chehelgerdi, Hamidreza Kabiri, Hosein Salehian-Dehkordi, Mohammad Abdolvand, Sharareh Salmanizadeh, Mohsen Rashidi, Anoosha Niazmand, Saba Ahmadi, Sara Feizbakhshan, Saber Kabiri, Nasimeh Vatandoost, Tayebeh Ranjbarnejad
Journal: Molecular Cancer (2023)

The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. The formation of cancer is a multifaceted process influenced by genetic, epigenetic, and environmental factors. iPSCs offer a distinctive platform for investigating the origin of cancer, paving the way for novel approaches to cancer treatment, drug testing, and tailored medical interventions. This review article will provide an overview of the science behind iPSCs, the current limitations and challenges in iPSC-based cancer therapy, the ethical and social implications, and the comparative analysis with other stem cell types for cancer treatment. The article will also discuss the applications of iPSCs in tumorigenesis, the future of iPSCs in tumorigenesis research, and highlight successful case studies utilizing iPSCs in tumorigenesis research. The conclusion will summarize the advancements made in iPSC-based tumorigenesis research and the importance of continued investment in iPSC research to unlock the full potential of these cells.
Hypersensitivity reactions to proton pump inhibitors. An <scp>EAACI</scp> position paper
Authors: Sevim Bavbek, Seçil Kepil Özdemir, Patrizia Bonadonna, Marina Atanaskovic‐Markovic, Annick Barbaud, Knut Brockow, Jose Laguna Martinez, Alla Nakonechna, Mauro Pagani, Alessandra Arcolacı, Carla Lombardo, Maria J. Torres
Journal: Allergy (2023)

Abstract Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dyspeptic diseases. In addition to their well‐known risk profile, PPI consumption is related to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around 1%–3%, due to the extraordinarily high rate of prescription and consumption of PPIs are related to a substantial risk. In this Position Paper, we provide clinicians with practical evidence‐based recommendations for the diagnosis and management of HSRs to PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more in‐depth investigations in the topic.
Osteonecrosis of the Femoral Head as a Potential Pitfall in 18F-PSMA-1007 PET
Authors: Matthieu Bailly, Nada Ibrahim, Elise Champeaux-Orange, Gilles Metrard
Journal: Clinical Nuclear Medicine (2023)

Abstract PSMA-targeted PET agents are mainly involved for prostate cancer; however, unspecific bone uptakes can be challenging for the clinician. We report the case of a 71-year-old man with history of recurrent prostate cancer initially treated by surgery and radiation therapy. 18 F-PSMA 1007 PET/CT was performed. Beside hyperfixing lymph nodes, focal uptake was found in right femoral head with shell subchondral hypofixation and no morphologic correlate on CT. MRI found bilateral osteonecrosis of the femoral head. This case emphasizes that osteonecrosis of the femoral head can mimic a metastasis uptake, even with normal CT, without however the fixation being constant.
68Ga-FAPI-04 PET/CT in Assessment of Fibroblast Activation in Keloids
Authors: Jiarou Wang, Nanze Yu, Guochang Wang, Rongxi Wang, Linlin Li, Yuanyuan Jiang, Huimin Sui, Yixin Sun, Zhijin Li, Xiao Long, Zhaohui Zhu
Journal: Clinical Nuclear Medicine (2023)

Purpose Keloids are benign fibroproliferative disorders characterized by the massive proliferation of fibroblasts. Fibroblast activation plays a key role in the invasive growth of keloids. Therefore, a prospective pilot study was conducted to explore the value of 68 Ga-FAPI-04 PET/CT in the assessment of keloids activity. Patients and Methods Twenty-five patients with keloid were enrolled to conduct 68 Ga-FAPI-04 PET/CT. All patients accepted surgery to remove part of the lesions within 1 week. SUV mean and SUV max were measured for semiquantitative analysis and compared with the Vancouver Scar Scale, Laser Speckle Contrast Imaging, pathology, and immunohistochemical stains. Results A total of 123 lesions were detected in 25 patients, most of which were distributed in the anterior chest wall. The 68 Ga-FAPI-04 uptake was significantly different at different sites ( P &lt; 0.0001). There was uptake heterogeneity within the keloid lesions, and a significant difference was found between the edge and center of some large lesions. The SUV max of 68 Ga-FAPI-04 showed significantly correlation with the Vancouver Scar Scale ( r = 0.565, P &lt; 0.0001) moderately and the Laser Speckle Contrast Imaging parameters mildly. The SUV max of 68 Ga-FAPI-04 had a moderate correlation with FAPI expression ( r = 0.520, P = 0.022). Moreover, collagen, fibroblast activator protein, and Ki-67 expression were found higher at the edges of keloid tissue than in the center. Conclusions 68 Ga-FAPI-04 PET/CT can reflect the distribution characteristics of activated fibroblasts in keloid tissue and may provide a novel method for keloid evaluation for further fibroblast-related therapies.
Prognostic Value of Baseline Tumor Burden and Tumor Dissemination Extracted From 18F-FDG PET/CT in a Cohort of Adult Patients With Early or Advanced Hodgkin Lymphoma
Authors: Mehdi Mouheb, Morgane Pierre-Jean, Anne Devillers, Christophe Fermé, Mohamed Benchalal, Guillaume Manson, Florence Le Jeune, Roch Houot, Xavier Palard-Novello
Journal: Clinical Nuclear Medicine (2023)

We aimed to assess the prognostic value of baseline tumor burden and dissemination parameters extracted from 18 F-FDG PET/CT in patients with early or advanced Hodgkin lymphoma (HL) treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or escalated BEACOPP (increased bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).
Chaetocin-mediated SUV39H1 inhibition targets stemness and oncogenic networks of diffuse midline gliomas and synergizes with ONC201
Authors: Dazhuan Eric Xin, Yunfei Liao, Rohit Rao, Sean Ogurek, Soma Sengupta, Mei Xin, Arman Esshaghi Bayat, William L Seibel, Richard T Graham, Carl Koschmann, Q Richard Lu
Journal: Neuro-Oncology (2023)

Abstract Background Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with extraordinarily limited treatment options and uniformly fatal prognosis. Histone H3K27M mutation is a common recurrent alteration in DIPG and disrupts epigenetic regulation. We hypothesize that genome-wide H3K27M-induced epigenetic dysregulation makes tumors vulnerable to epigenetic targeting. Methods We performed a screen of compounds targeting epigenetic enzymes to identify potential inhibitors for the growth of patient-derived DIPG cells. We further carried out transcriptomic and genomic landscape profiling including RNA-seq and CUT&amp;RUN-seq as well as shRNA-mediated knockdown to assess the effects of chaetocin and SUV39H1, a target of chaetocin, on DIPG growth. Results High-throughput small-molecule screening identified an epigenetic compound chaetocin as a potent blocker of DIPG cell growth. Chaetocin treatment selectively decreased proliferation and increased apoptosis of DIPG cells and significantly extended survival in DIPG xenograft models, while restoring H3K27me3 levels. Moreover, the loss of H3K9 methyltransferase SUV39H1 inhibited DIPG cell growth. Transcriptomic and epigenomic profiling indicated that SUV39H1 loss or inhibition led to the downregulation of stemness and oncogenic networks including growth factor receptor signaling and stemness-related programs; however, D2 dopamine receptor (DRD2) signaling adaptively underwent compensatory upregulation conferring resistance. Consistently, a combination of chaetocin treatment with a DRD2 antagonist ONC201 synergistically increased the antitumor efficacy. Conclusions Our studies reveal a therapeutic vulnerability of DIPG cells through targeting the SUV39H1–H3K9me3 pathway and compensatory signaling loops for treating this devastating disease. Combining SUV39H1-targeting chaetocin with other agents such as ONC201 may offer a new strategy for effective DIPG treatment.
Extracellular vesicles in degenerative retinal diseases: A new therapeutic paradigm
Authors: Federico Manai, Adrian Smedowski, Kai Kaarniranta, Sergio Comincini, Marialaura Amadio
Journal: Journal of Controlled Release (2023)

Nanoscale extracellular vesicles (EVs), consisting of exomers, exosomes and microvesicles/ectosomes, have been extensively investigated in the last 20 years, although their biological role is still something of a mystery. EVs are involved in the transfer of lipids, nucleic acids and proteins from donor to recipient cells or distant organs as well as regulating cell-cell communication and signaling. Thus, EVs are important in intercellular communication and this is not limited to sister cells, but may also mediate the crosstalk between different cell types even over long distances. EVs play crucial functions in both cellular homeostasis and the pathogenesis of diseases, and since their contents reflect the status of the donor cell, they represent an additional valuable source of information for characterizing complex biological processes. Recent advances in isolation and analytical methods have led to substantial improvements in both characterizing and engineering EVs, leading to their use either as novel biomarkers for disease diagnosis/prognosis or even as novel therapies. Due to their capacity to carry biomolecules, various EV-based therapeutic applications have been devised for several pathological conditions, including eye diseases. In the eye, EVs have been detected in the retina, aqueous humor, vitreous body and also in tears. Experiences with other forms of intraocular drug applications have opened new ways to use EVs in the treatment of retinal diseases. We here provide a comprehensive summary of the main in vitro, in vivo, and ex vivo literature-based studies on EVs' role in ocular physiological and pathological conditions. We have focused on age-related macular degeneration, diabetic retinopathy, glaucoma, which are common eye diseases leading to permanent blindness, if not treated properly. In addition, the putative use of EVs in retinitis pigmentosa and other retinopathies is discussed. Finally, we have reviewed the potential of EVs as therapeutic tools and/or biomarkers in the above-mentioned retinal disorders. Evidence emerging from experimental disease models and human material strongly suggests future diagnostic and/or therapeutic exploitation of these biological agents in various ocular disorders with a good possibility to improve the patient's quality of life.